General Information About Laryngeal Cancer

Incidence and Mortality

Estimated new cases and deaths from laryngeal cancer in the United States in 2024:[1]

• New cases: 12,650.
• Deaths: 3,880.

Anatomy

The larynx is divided into the following three anatomical regions:

• The supraglottic larynx includes the epiglottis, false vocal cords, ventricles, aryepiglottic folds, and arytenoids.
• The glottis includes the true vocal cords and the anterior and posterior commissures.
• The subglottic region begins about 1 cm below the true vocal cords and extends to the lower border of the cricoid cartilage or the first tracheal ring.

The supraglottic area is rich in lymphatic drainage. After penetrating the pre-epiglottic space and thyrohyoid membrane, lymphatic drainage is initially to the jugulodigastric and midjugular nodes. About 25% to 50% of patients present with involved lymph nodes. The precise figure depends on the T (tumor) stage. The true vocal cords are devoid of lymphatics. As a result, vocal cord cancer confined to the true cords rarely, if ever, presents with involved lymph nodes. Extension above or below the cords may, however, lead to lymph node involvement. Primary subglottic cancers, which are quite rare, drain through the cricothyroid and cricotracheal membranes to the pretracheal, paratracheal, and inferior jugular nodes, and occasionally to mediastinal nodes.[2]

Risk Factors

There is a clear association among smoking, excess alcohol ingestion, and the development of squamous cell cancers of the upper aerodigestive tract.[3] For smokers, the risk of laryngeal cancer decreases after they stop smoking but remains elevated, even years later, compared with that of nonsmokers.[4] If a patient who has had a single cancer continues to smoke and drink alcoholic beverages, the likelihood of a cure for the initial cancer, by any modality, is diminished, and the risk of second tumor is enhanced. Because of clinical problems related to smoking and alcohol use in this population, many patients die of intercurrent illness rather than the primary cancer.

Clinical Features

Supraglottic cancers typically present with sore throat, painful swallowing, referred ear pain, change in voice quality, or enlarged neck nodes. Early vocal cord cancers are usually detected because of hoarseness. By the time they are detected, cancers arising in the subglottic area commonly involve the vocal cords; thus, symptoms usually relate to contiguous spread.

Prognostic Factors

The most important adverse prognostic factors for laryngeal cancers include increasing T stage and N (regional lymph node) stage. Other prognostic factors may include sex, age, performance status, and a variety of pathological features of the tumor, including grade and depth of invasion.[5]

Prognosis for small laryngeal cancers that have not spread to lymph nodes is very good. Cure rates are 75% to 95% depending on the site, tumor bulk,[6] and degree of infiltration. Although most patients with early lesions can be cured by either radiation therapy or surgery, radiation therapy may be reasonable to preserve the voice, leaving surgery for salvage. Patients with a preradiation hemoglobin level higher than 13 g/dL have higher local control and survival rates than patients who are anemic.[7]

Locally advanced lesions are treated with combined modality treatment involving radiation and chemotherapy with or without surgery. The aim is laryngeal preservation in appropriately selected candidates.[8] Distant metastases are also common, even if the primary tumor is controlled.

Intermediate lesions have intermediate prognoses, depending on the site, T stage, N stage, and performance status. Therapy recommendations for patients with these lesions are based on a variety of complex anatomical, clinical, and social factors, which should be individualized and discussed in multidisciplinary consultation (surgery, radiation therapy, and dental and oral surgery) prior to prescribing therapy.

Follow-Up and Survivorship

Second primary tumors, often in the aerodigestive tract, have been reported in as many as 25% of patients whose initial lesion is controlled. A study has shown that daily treatment of these patients with moderate doses of isotretinoin (i.e., 13-cis-retinoic acid) for 1 year can significantly reduce the incidence of second tumors.[9] No survival advantage has been demonstrated, partially because of recurrence and death from the primary malignancy.

Patients treated for laryngeal cancers are at the highest risk of recurrence in the first 2 to 3 years. Recurrences after 5 years are rare and usually represent new primary malignancies. Close, regular follow-up is crucial to maximize the chance for salvage. Follow-up includes careful clinical examination and repetition of any abnormal staging study, along with attention to any treatment-related toxic effect or complication.

References:

1. American Cancer Society: Cancer Facts and Figures 2024. American Cancer Society, 2024. Available online. Last accessed June 21, 2024.
2. Spaulding CA, Hahn SS, Constable WC: The effectiveness of treatment of lymph nodes in cancers of the pyriform sinus and supraglottis. Int J Radiat Oncol Biol Phys 13 (7): 963-8, 1987.
3. Spitz MR: Epidemiology and risk factors for head and neck cancer. Semin Oncol 21 (3): 281-8, 1994.
4. Bosetti C, Garavello W, Gallus S, et al.: Effects of smoking cessation on the risk of laryngeal cancer: an overview of published studies. Oral Oncol 42 (9): 866-72, 2006.
5. Yilmaz T, HoÅŸal S, Gedikoglu G, et al.: Prognostic significance of depth of invasion in cancer of the larynx. Laryngoscope 108 (5): 764-8, 1998.
6. Reddy SP, Mohideen N, Marra S, et al.: Effect of tumor bulk on local control and survival of patients with T1 glottic cancer. Radiother Oncol 47 (2): 161-6, 1998.
7. Fein DA, Lee WR, Hanlon AL, et al.: Pretreatment hemoglobin level influences local control and survival of T1-T2 squamous cell carcinomas of the glottic larynx. J Clin Oncol 13 (8): 2077-83, 1995.
8. Forastiere AA, Zhang Q, Weber RS, et al.: Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 31 (7): 845-52, 2013.
9. Hong WK, Lippman SM, Itri LM, et al.: Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 323 (12): 795-801, 1990.

Cellular Classification of Laryngeal Cancer

Most laryngeal cancers are of squamous cell histology. Squamous cell subtypes include keratinizing and nonkeratinizing and well-differentiated to poorly differentiated grade. A variety of nonsquamous cell laryngeal cancers also occur.[1] These are not staged using the American Joint Cancer Committee staging system, and their management, which is not discussed here, can differ from that of squamous cell laryngeal cancers. In situ squamous cell carcinoma of the larynx is usually managed by a conservative surgical procedure such as mucosal stripping or superficial laser excision. Radiation therapy may also be appropriate treatment of selected patients with in situ carcinoma of the glottic larynx.

References:

1. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.

Stage Information for Laryngeal Cancer

The staging system for laryngeal cancer is clinical and based on the best possible estimate of the extent of disease before treatment. The assessment of the primary tumor is based on inspection and palpation, when possible, and by fiberoptic laryngoscopy. Panendoscopy under anesthesia ensures careful clinical examination to determine clinical extent of local disease. The tumor must be confirmed histologically, and any other pathological data obtained on biopsy may be included. Head and neck magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography should be done before therapy to supplement inspection and palpation.[1] Additional radiographic studies may be included. The appropriate nodal drainage areas in the neck should be examined by careful palpation.

Definitions of TNM

The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification to define laryngeal cancer.[2]

AJCC Prognostic Stage Groups

References:

1. Thabet HM, Sessions DG, Gado MH, et al.: Comparison of clinical evaluation and computed tomographic diagnostic accuracy for tumors of the larynx and hypopharynx. Laryngoscope 106 (5 Pt 1): 589-94, 1996.
2. Larynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 149-61.

Treatment Option Overview for Laryngeal Cancer

Surgery and/or Radiation Therapy

Surgery and radiation therapy have been the standards for treatment of laryngeal cancer. However, outcome data from randomized trials are limited. Studies have attempted to evaluate the use of surgery or radiation but have been underpowered.[1] Selection of primary surgery versus radiation therapy–based treatment should be made in a multidisciplinary setting with consideration of disease stage, comorbidities, and functional status, including voice and swallowing outcomes and lung capacity.

Small superficial cancers without laryngeal fixation or lymph node involvement are successfully treated by radiation therapy or surgery alone, including laser excision surgery. Radiation therapy may be selected to preserve the voice and to reserve surgery for salvaging failures. The radiation field and dose are determined by the location and size of the primary tumor. A variety of curative surgical procedures are also recommended for laryngeal cancers, some of which preserve vocal function. An appropriate surgical procedure must be considered for each patient, given the anatomical problem, performance status, and clinical expertise of the treatment team. Advanced laryngeal cancers are often treated by combining radiation with concurrent chemotherapy for larynx preservation and total laryngectomy for bulky T4 disease or salvage.[2,3,4]

Evaluation of treatment outcome can be reported in various ways: locoregional control, disease-free survival, determinate survival, and overall survival (OS) at 2 to 5 years. Preservation of voice is an important parameter to evaluate. Outcome should be reported after initial surgery, initial radiation, planned combined treatment, or surgical salvage of radiation failures. Primary source material should be consulted to review these differences.

A review of published clinical results of definitive radiation therapy for head and neck cancer suggests a significant loss of local control when the administration of radiation therapy was prolonged. Therefore, extending standard treatment schedules should be avoided whenever possible.[5,6]

The results of radiation therapy have not been directly compared with those of endolaryngeal surgery (with or without laser) for patients with early-stage laryngeal cancer. The evidence is insufficient to show a clear difference in local control or OS for these two treatment options. Retrospective data suggest, compared with surgery, radiation therapy might cause less perturbation of voice quality without a significant difference in patient perception.[7]

Concurrent Chemoradiation Therapy

Concurrent chemoradiation therapy is a standard treatment option for patients with locally advanced (stage III and stage IV) laryngeal cancer.

Evidence (concurrent chemoradiation therapy):

1. A meta-analysis of 93 randomized prospective head and neck cancer trials published between 1965 and 2000 showed the following:[8][Level of evidence B4]
   • The subset of patients receiving chemotherapy and radiation therapy had a 4.5% absolute survival advantage.
   • Patients who received concurrent chemotherapy had a greater survival benefit than those who received neoadjuvant chemotherapy.
2. In a randomized trial of patients with locally advanced head and neck cancer, curative-intent radiation therapy alone (213 patients) was compared with radiation therapy plus weekly cetuximab (211 patients).[9] The initial dose of cetuximab was 400 mg/m² of body-surface area 1 week before radiation therapy was started, followed by a weekly dose of 250 mg/m² of body-surface area for the duration of the radiation therapy. This study allowed altered-fractionation regimens to be used in both arms.[9,10][Level of evidence A1]
   • At a median follow-up of 54 months, patients treated with cetuximab and radiation therapy demonstrated significantly higher progression-free survival (PFS) (hazard ratio [HR] for disease progression or death, 0.70; P = .006).
   • Patients in the cetuximab arm experienced higher rates of acneiform rash and infusion reactions, although the incidence of other grade 3 or higher toxicities, including mucositis, did not differ significantly between the two groups.

For more information about oral toxicities, see Oral Complications of Cancer Therapies.

Neoadjuvant Chemotherapy Followed by Concurrent Chemoradiation Therapy

In a meta-analysis of five randomized trials, a total of 1,022 patients with locally advanced head and neck squamous cell cancer were randomly assigned to receive either neoadjuvant chemotherapy with TPF (docetaxel, cisplatin, and fluorouracil) followed by concurrent chemoradiation therapy or concurrent chemoradiation therapy alone. The analysis failed to show an OS (HR, 1.01; 95% confidence limits [CLs], 0.84–1.21; P = .92) or PFS (HR, 0.91; 95% CLs, 0.75–1.1; P = .32) advantage for neoadjuvant chemotherapy using the TPF regimen over concurrent chemoradiation therapy alone.[11][Level of evidence A1]

Evidence (neoadjuvant chemotherapy followed by concurrent chemoradiation therapy):

1. The Department of Veterans Affairs (VA) Laryngeal Cancer Study Group directly compared chemotherapy followed by radiation therapy versus up-front surgery with postoperative radiation therapy. A total of 332 patients were randomly assigned to either three cycles of chemotherapy (cisplatin and fluorouracil) and radiation therapy or surgery and radiation therapy.[12]
   • After two cycles of chemotherapy, the clinical tumor response was complete in 31% of the patients, and there was a partial response in 54% of the patients. Survival was similar in both arms; however, larynx preservation was possible in 64% of the patients in the chemotherapy-followed-by-radiation therapy arm.
2. The VA study was followed by a randomized study, RTOG 9111 (NCT00002496), in which the laryngeal preservation arm of the VA study was compared with the concurrent chemoradiation therapy and radiation therapy-alone arms. The primary end point was laryngectomy-free survival.[4] RTOG 9111 evaluated 547 patients with locally advanced laryngeal cancer who were enrolled between August 1992 and May 2000, with a median follow-up for surviving patients of 10.8 years (range, 0.07–17 years). Three regimens were compared, including neoadjuvant chemotherapy plus radiation therapy, concurrent chemoradiation therapy, and radiation therapy alone.
   • Both chemotherapy regimens improved laryngectomy-free survival compared with radiation therapy alone (neoadjuvant chemotherapy vs. radiation therapy alone, HR, 0.75; 95% confidence interval [CI], 0.59–0.95; P = .02; concurrent chemotherapy vs. radiation therapy alone, HR, 0.78; 95% CI, 0.78–0.98; P = .03).
   • Concurrent radiation therapy plus cisplatin resulted in a statistically significantly higher percentage of patients with an intact larynx at 10 years (67.5% for patients who had neoadjuvant chemotherapy; 81.7% for patients who had concurrent chemotherapy; and 63.8% for patients who received radiation therapy alone); 80% of laryngectomies were performed during the first 2 years (84 laryngectomies during year 1 and 35 laryngectomies during year 2).
   • Concurrent cisplatin with radiation therapy resulted in a 41% reduction in risk of locoregional failure compared with radiation therapy alone (HR, 0.59; 95% CI, 0.43–0.82; P = .0015) and a 34% reduction in risk compared with neoadjuvant chemotherapy (HR, 0.66; 95% CI, 0.48–0.92; P = .004). Both chemotherapy regimens had a lower incidence of distant metastases, although this did not reach statistical significance compared with radiation therapy alone.
   • The 10-year cumulative rates of late toxicity (grades 3–5) were 30.6% for neoadjuvant chemotherapy, 33.3% for concurrent chemotherapy, and 38% for radiation therapy alone, and were not significantly different between the arms.
   • OS was not significantly different between the groups, although there was possibly a worse outcome in the concurrent groups compared with the neoadjuvant chemotherapy group (HR, 1.25; 95% CI, 0.98–1.61; P = .08). The OS rates were 58% (5 year) and 39% (10 year) for neoadjuvant chemotherapy, 55% (5 year) and 28% (10 year) for concurrent chemoradiation therapy, and 54% (5 year) and 32% (10 year) for radiation therapy alone.
   • The number of deaths not attributed to larynx cancer or treatment were higher with concurrent chemotherapy (30.8% vs. 20.8% with neoadjuvant chemotherapy and 16.9% with radiation alone), because after approximately 4.5 years, the survival curves began to separate and favor neoadjuvant chemotherapy, although the difference was not statistically significant.

Fluorouracil dosing

The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[13,14] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[13,14,15] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient's DPYD genotype and number of functioning DPYD alleles.[16,17,18]DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[19] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[20]

Altered Fractionation Versus Standard Fractionation Radiation Therapy

Radiation therapy alone with altered fractionation may be used for patients with locally advanced laryngeal cancer who are not candidates for chemotherapy. Altered fractionation radiation therapy yields a higher locoregional control rate compared with standard fractionated radiation therapy for patients with stage III and stage IV head and neck cancer.

Evidence (altered fractionation vs. standard fractionation radiation therapy):

1. The randomized RTOG-9003 trial (NCT00771641) included four radiation therapy treatment arms:[21,22][Level of evidence A1]
   • Standard fractionation (SFX) to 70 Gy in 35 daily fractions for 7 weeks.
   • Hyperfractionation (HFX) to 81.6 Gy in 68 twice-daily fractions for 7 weeks.
   • Accelerated fractionation split course (AFX-S) to 67.2 Gy in 42 fractions for 6 weeks with a 2-week rest after 38.4 Gy.
   • Accelerated concurrent boost fractionation (AFX-C) to 72 Gy in 42 fractions for 6 weeks.

   In a long-term analysis, the three investigational arms were compared with SFX.

   • Only the HFX arm showed superior locoregional control and survival at 5 years compared with the SFX arm (HR, 0.79; 95% CI, 0.62–1.00; P = .05).
   • AFX-C was associated with increased late toxicity compared with SFX.
2. The following results were shown in a meta-analysis of 15 randomized trials with a total of 6,515 patients and a median follow-up of 6 years involving the assessment of HFX or AFX-S for patients with stage III and stage IV oropharyngeal cancer:[23][Level of evidence A1]
   • There was a significant survival benefit with altered-fractionated radiation therapy and a 3.4% absolute benefit at 5 years (HR, 0.92; 95% CI, 0.86–0.97; P = .003).
   • Altered-fractionation radiation therapy improves locoregional control, with greater benefit shown in younger patients.
   • HFX demonstrated a greater survival benefit (8% at 5 years) than did AFX-S (2% with accelerated fractionation without total dose-reduction and 1.7% with total dose-reduction at 5 years; P = .02).

An additional late effect from radiation therapy is hypothyroidism, which occurs in 30% to 40% of patients who have received external-beam radiation therapy to the entire thyroid gland. Thyroid function testing of patients is a consideration before therapy and as part of posttreatment follow-up.[24,25]

Prospective data from two randomized controlled trials reported the incidence of hypothyroidism.[26]

• At a median follow-up of 41 months, 55.1% of the patients developed hypothyroidism (39.3% subclinical, 15.7% biochemical).
• Patients who underwent intensity-modulated radiation therapy (IMRT) had higher subclinical hypothyroidism (51.1% vs. 27.3%; P = .021), peaking around 1 year after radiation therapy.
• Younger age, hypopharynx/larynx primary, node positivity, higher dose/fraction (IMRT arm), and D100 were statistically significant factors for developing hypothyroidism.[26][Level of evidence A3]

For patients with well-lateralized oropharyngeal cancer, such as a T1 or T2 tonsil primary tumor with limited extension into the palate or tongue base and limited ipsilateral lymph node involvement without extracapsular extension, elective treatment to the ipsilateral lymph nodes results in only minimal risk of spread to the contralateral neck.[27] For T3 and T4 tumors that are midline or approach the midline, bilateral nodal treatment is a consideration. In addition to the cervical lymph node chain, retropharyngeal lymph nodes can also be encompassed in the elective nodal treatment.

Surgery Followed by Postoperative Radiation Therapy (PORT) With or Without Chemotherapy for Patients With Locally Advanced Disease

New surgical techniques for resection and reconstruction that provide access and functional preservation have extended the surgical options for patients with stage III or stage IV laryngeal cancer. Specific surgical procedures and their modifications are not described here because of the wide variety of surgical approaches, the variety of opinions about the role of modified neck dissections, and the multiple reconstructive techniques that may give the same results. This group of patients is managed by head and neck surgeons who are skilled in the multiple procedures available and are actively and frequently involved in the care of these patients.

Depending on pathological findings after primary surgery, PORT with or without chemotherapy is used in the adjuvant setting for the following histological findings:

• T4 disease.
• Perineural invasion.
• Lymphovascular invasion.
• Positive margins or margins less than 5 mm.
• Extracapsular extension of a lymph node.
• Two or more involved lymph nodes.

The addition of chemotherapy to PORT for laryngeal cancer squamous cell carcinoma demonstrates a locoregional control and OS benefit compared with radiation therapy alone in patients who have high-risk pathological risk factors, extracapsular extension of a lymph node, or positive margins, based on a pooled analysis of the EORTC-22931 [NCT00002555] and RTOG-9501 [NCT00002670] studies.[28,29,30,31][Level of evidence A1]

For patients with intermediate pathological risk factors, the addition of cisplatin chemotherapy given concurrently with PORT is unclear. Intermediate pathological risk factors include:

• T3 and T4 disease (or stage III and stage IV disease).
• Perineural infiltration.
• Vascular embolisms.
• Clinically enlarged level IV–V lymph nodes secondary to tumors arising in the oral cavity or oropharynx.
• Two or more histopathologically involved lymph nodes without extracapsular extension.
• Close margins less than 5 mm.

The addition of cetuximab with radiation therapy in the postoperative setting for these intermediate pathological risk factors is being tested in a randomized trial (RTOG-0920 [NCT00956007]).

The incidence of lymph node metastases in patients with stage I glottic cancer ranges from 0% to 2%; for more advanced disease, such as stage II, 10%; and for stage III glottic, 15%. Thus, there is no need to treat glottic cancer cervical lymph nodes electively in patients with stage I tumors and small stage II tumors. Elective neck radiation is a consideration for T3 or T4 glottic tumors or T1 to T4 supraglottic tumors.[32]

For patients with cancer of the subglottis, combined modality therapy is generally preferred for the uncommon small lesions (i.e., stage I or stage II); however, radiation therapy alone may be used.

Patients who smoke during radiation therapy appear to have lower response rates and shorter survival durations than those who do not.[33] Such patients should be counseled on smoking cessation before beginning radiation therapy.

References:

1. Iyer NG, Tan DS, Tan VK, et al.: Randomized trial comparing surgery and adjuvant radiotherapy versus concurrent chemoradiotherapy in patients with advanced, nonmetastatic squamous cell carcinoma of the head and neck: 10-year update and subset analysis. Cancer 121 (10): 1599-607, 2015.
2. Silver CE, Ferlito A: Surgery for Cancer of the Larynx and Related Structures. 2nd ed. Saunders, 1996.
3. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
4. Forastiere AA, Zhang Q, Weber RS, et al.: Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 31 (7): 845-52, 2013.
5. Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23 (2): 457-67, 1992.
6. Hansen O, Overgaard J, Hansen HS, et al.: Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: dependency on tumor differentiation. Radiother Oncol 43 (1): 47-51, 1997.
7. Yoo J, Lacchetti C, Hammond JA, et al.: Role of endolaryngeal surgery (with or without laser) compared with radiotherapy in the management of early (T1) glottic cancer: a clinical practice guideline. Curr Oncol 20 (2): e132-5, 2013.
8. Pignon JP, le Maître A, Maillard E, et al.: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92 (1): 4-14, 2009.
9. Bonner JA, Harari PM, Giralt J, et al.: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354 (6): 567-78, 2006.
10. Curran D, Giralt J, Harari PM, et al.: Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol 25 (16): 2191-7, 2007.
11. Budach W, Bölke E, Kammers K, et al.: Induction chemotherapy followed by concurrent radio-chemotherapy versus concurrent radio-chemotherapy alone as treatment of locally advanced squamous cell carcinoma of the head and neck (HNSCC): A meta-analysis of randomized trials. Radiother Oncol 118 (2): 238-43, 2016.
12. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 324 (24): 1685-90, 1991.
13. Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021.
14. Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016.
15. Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021.
16. Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018.
17. Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018.
18. Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022.
19. Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022.
20. Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023.
21. Fu KK, Pajak TF, Trotti A, et al.: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 48 (1): 7-16, 2000.
22. Beitler JJ, Zhang Q, Fu KK, et al.: Final results of local-regional control and late toxicity of RTOG 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys 89 (1): 13-20, 2014.
23. Baujat B, Bourhis J, Blanchard P, et al.: Hyperfractionated or accelerated radiotherapy for head and neck cancer. Cochrane Database Syst Rev (12): CD002026, 2010.
24. Turner SL, Tiver KW, Boyages SC: Thyroid dysfunction following radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 31 (2): 279-83, 1995.
25. Constine LS: What else don't we know about the late effects of radiation in patients treated for head and neck cancer? Int J Radiat Oncol Biol Phys 31 (2): 427-9, 1995.
26. Murthy V, Narang K, Ghosh-Laskar S, et al.: Hypothyroidism after 3-dimensional conformal radiotherapy and intensity-modulated radiotherapy for head and neck cancers: prospective data from 2 randomized controlled trials. Head Neck 36 (11): 1573-80, 2014.
27. O'Sullivan B, Warde P, Grice B, et al.: The benefits and pitfalls of ipsilateral radiotherapy in carcinoma of the tonsillar region. Int J Radiat Oncol Biol Phys 51 (2): 332-43, 2001.
28. Cooper JS, Pajak TF, Forastiere AA, et al.: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350 (19): 1937-44, 2004.
29. Bernier J, Domenge C, Ozsahin M, et al.: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350 (19): 1945-52, 2004.
30. Bernier J, Cooper JS, Pajak TF, et al.: Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 27 (10): 843-50, 2005.
31. Cooper JS, Zhang Q, Pajak TF, et al.: Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 84 (5): 1198-205, 2012.
32. Spaulding CA, Hahn SS, Constable WC: The effectiveness of treatment of lymph nodes in cancers of the pyriform sinus and supraglottis. Int J Radiat Oncol Biol Phys 13 (7): 963-8, 1987.
33. Browman GP, Wong G, Hodson I, et al.: Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 328 (3): 159-63, 1993.

Treatment of Stage I Laryngeal Cancer

Supraglottis

Treatment options for stage I cancer of the supraglottis include the following:

1. External-beam radiation therapy (EBRT) therapy alone.
2. Supraglottic laryngectomy. Total laryngectomy may be reserved for patients unable to tolerate potential respiratory complications of surgery or the supraglottic laryngectomy.

Glottis

Treatment options for stage I cancer of the glottis include the following:

1. Radiation therapy.[1,2,3,4]
2. Endoscopic CO₂ laser excision.[5]
3. Cordectomy for very carefully selected patients with limited and superficial T1 lesions.[6,7]
4. Partial or hemilaryngectomy or total laryngectomy, depending on anatomical considerations.

Subglottis

Treatment options for stage I cancer of the subglottis include the following:

1. Lesions can be treated successfully by radiation therapy alone with preservation of normal voice.
2. Surgery is reserved for failure of radiation therapy or for patients who cannot be easily assessed for radiation therapy.

For more information, see the Treatment Option Overview for Laryngeal Cancer section.

Radiation therapy

Transoral CO₂ laser excision versus EBRT

Selection of treatment should include an evaluation of voice function and quality after treatment. Endoscopic CO₂ laser resections may also achieve similar results in terms of local control and function [8] compared with radiation therapy, although no randomized studies have been performed.[9]

Evidence (transoral CO₂ laser excision vs. EBRT):

1. A meta-analysis examined oncologic control in 22 consecutive case series.
   • No clear differences were demonstrated between transoral CO₂ laser excision and EBRT in terms of local control (odds ratio [OR], 0.81; 95% confidence interval [CI], 0.51–1.3) and laryngectomy-free survival (OR, 0.84; 95% CI, 0.42–1.66).
   • There was a trend for improved posttreatment voice quality with radiation therapy. Transoral CO₂ laser–excision surgery dominates radiation therapy from a cost-utility standpoint.[5][Level of evidence B4]

Conventional radiation therapy versus hypofractionated radiation therapy

Conventional and hypofractionated radiation therapy regimens have been studied regarding radiation-dose fractionation for patients with early-stage larynx cancer.

Evidence (conventional radiation therapy vs. hypofractionated radiation therapy):

1. In a randomized study of patients with early-stage larynx cancer, patients were assigned to standard fractionation in 2 Gy daily fractions or a hypofractionated regimen of 2.25 Gy daily; 82 patients were allocated to a conventional fractionation (CONV) arm (66 Gy/33 fractions for T1 and 70 Gy/35 fractions for T2), with 74 patients to the hypofractionation (HYPO) arm (63 Gy/28 fractions for T1 and 67.5 Gy/30 fractions for T2).[10] The study was underpowered and closed early because of a lack of accrual, although no statistically significant differences were seen between treatment arms in terms of local progression-free survival (PFS).
   • With a median follow-up of 67 months (range, 2–122 months), the 5-year local PFS rate was 77.8% for the CONV arm and 88.5% for the HYPO arm (hazard ratio [HR], 1.55; P = .213).
   • No significant difference was observed in the toxicity profile between the two arms.
   • In a subgroup exploratory analysis for T1a disease, the 5-year local PFS rate trended positively in the HYPO arm (76.7% vs. 93.0%; HR, 3.65; P = .056).[10][Level of evidence B1]

   Earlier single-institution reports support hypofractionated regimens using 2.25 Gy per fraction for early T1 and T2 larynx cancer with high local control rates.[11][Level of evidence C3]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Mittal B, Rao DV, Marks JE, et al.: Role of radiation in the management of early vocal cord carcinoma. Int J Radiat Oncol Biol Phys 9 (7): 997-1002, 1983.
2. Wang CC: Factors influencing the success of radiation therapy for T2 and T3 glottic carcinomas. Importance of cord mobility and sex. Am J Clin Oncol 9 (6): 517-20, 1986.
3. Mendenhall WM, Amdur RJ, Morris CG, et al.: T1-T2N0 squamous cell carcinoma of the glottic larynx treated with radiation therapy. J Clin Oncol 19 (20): 4029-36, 2001.
4. Foote RL, Olsen KD, Kunselman SJ, et al.: Early-stage squamous cell carcinoma of the glottic larynx managed with radiation therapy. Mayo Clin Proc 67 (7): 629-36, 1992.
5. Higgins KM: What treatment for early-stage glottic carcinoma among adult patients: CO2 endolaryngeal laser excision versus standard fractionated external beam radiation is superior in terms of cost utility? Laryngoscope 121 (1): 116-34, 2011.
6. Steiner W: Results of curative laser microsurgery of laryngeal carcinomas. Am J Otolaryngol 14 (2): 116-21, 1993 Mar-Apr.
7. Olsen KD, Thomas JV, DeSanto LW, et al.: Indications and results of cordectomy for early glottic carcinoma. Otolaryngol Head Neck Surg 108 (3): 277-82, 1993.
8. Agrawal A, Moon J, Davis RK, et al.: Transoral carbon dioxide laser supraglottic laryngectomy and irradiation in stage I, II, and III squamous cell carcinoma of the supraglottic larynx: report of Southwest Oncology Group Phase 2 Trial S9709. Arch Otolaryngol Head Neck Surg 133 (10): 1044-50, 2007.
9. Dey P, Arnold D, Wight R, et al.: Radiotherapy versus open surgery versus endolaryngeal surgery (with or without laser) for early laryngeal squamous cell cancer. Cochrane Database Syst Rev (2): CD002027, 2002.
10. Fein DA, Mendenhall WM, Parsons JT, et al.: T1-T2 squamous cell carcinoma of the glottic larynx treated with radiotherapy: a multivariate analysis of variables potentially influencing local control. Int J Radiat Oncol Biol Phys 25 (4): 605-11, 1993.
11. Moon SH, Cho KH, Chung EJ, et al.: A prospective randomized trial comparing hypofractionation with conventional fractionation radiotherapy for T1-2 glottic squamous cell carcinomas: results of a Korean Radiation Oncology Group (KROG-0201) study. Radiother Oncol 110 (1): 98-103, 2014.

Treatment of Stage II Laryngeal Cancer

Supraglottis

Treatment options for stage II cancer of the supraglottis include the following:

1. External-beam radiation therapy alone for the smaller lesions encompassing the primary disease and regional elective nodes.[1]
2. Supraglottic laryngectomy with bilateral neck dissections, depending on location of the lesion, clinical status of the patient, and expertise of the treatment team. Careful selection must be made to ensure adequate pulmonary and swallowing function postoperatively.
3. Postoperative radiation therapy (PORT) is indicated for positive or close surgical margins or other adverse pathological risk factors.

Radiation therapy should be preferred because of the good results, preservation of the voice, and the possibility of surgical salvage in patients whose disease recurs locally.

Glottis

Treatment options for stage II cancer of the glottis include the following:

1. Radiation therapy.[1,2,3,4]
2. Endoscopic CO₂ laser excision.[5]
3. Partial or hemilaryngectomy or total laryngectomy, depending on anatomic considerations. Under certain circumstances, laser microsurgery may be appropriate.[6]

Subglottis

Treatment options for stage II cancer of the subglottis include the following:

1. Lesions can be treated successfully by radiation therapy alone with preservation of normal voice.[1]
2. Surgery is reserved for failure of radiation therapy or for patients in whom follow-up is likely to be difficult.

For more information, see the Treatment Option Overview for Laryngeal Cancer section.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
2. Mittal B, Marks JE, Ogura JH: Transglottic carcinoma. Cancer 53 (1): 151-61, 1984.
3. Medini E, Medini I, Lee CK, et al.: Curative radiotherapy for stage II-III squamous cell carcinoma of the glottic larynx. Am J Clin Oncol 21 (3): 302-5, 1998.
4. Mendenhall WM, Amdur RJ, Morris CG, et al.: T1-T2N0 squamous cell carcinoma of the glottic larynx treated with radiation therapy. J Clin Oncol 19 (20): 4029-36, 2001.
5. Higgins KM: What treatment for early-stage glottic carcinoma among adult patients: CO2 endolaryngeal laser excision versus standard fractionated external beam radiation is superior in terms of cost utility? Laryngoscope 121 (1): 116-34, 2011.
6. Steiner W: Results of curative laser microsurgery of laryngeal carcinomas. Am J Otolaryngol 14 (2): 116-21, 1993 Mar-Apr.

Treatment of Stage III Laryngeal Cancer

Supraglottis

Treatment options for stage III cancer of the supraglottis include the following:

1. Concurrent chemoradiation therapy can be considered for patients who would require total laryngectomy for control of disease.[1]
2. Neoadjuvant chemotherapy followed by concurrent chemoradiation therapy. Laryngectomy is reserved for patients with less than a 50% response to chemotherapy or who have persistent disease following radiation.[1,2,3,4,5,6][Level of evidence A3]
3. Definitive radiation therapy alone with altered fractionation in patients who are not candidates for concurrent chemotherapy and surgery (total laryngectomy) for salvage of radiation failures.[7]
4. Surgery with or without postoperative radiation therapy (PORT).[8]

Glottis

Treatment options for stage III cancer of the glottis include the following:

1. Concurrent chemoradiation therapy can be considered for patients who would require total laryngectomy for control of disease.[1]
2. Neoadjuvant chemotherapy followed by concurrent chemoradiation therapy. Laryngectomy is reserved for patients with less than a 50% response to chemotherapy or who have persistent disease after radiation.[1,2,3,4,5,6]
3. Definitive radiation therapy alone with altered fractionation in patients who are not candidates for concurrent chemotherapy and surgery (total laryngectomy) for salvage of radiation failures.[7]
4. Surgery with or without PORT.[8]
5. Clinical trials exploring novel targeted therapy, immunotherapy, novel chemotherapy, radiosensitizers, or particle-beam radiation therapy.[9]

Subglottis

Treatment options for stage III cancer of the subglottis include the following:

1. Laryngectomy plus isolated thyroidectomy and tracheoesophageal node dissection usually followed by PORT.[10]
2. Treatment by radiation therapy alone is indicated for patients who are not candidates for surgery. Patients should be closely followed, and surgical salvage should be planned for recurrences that are local or in the neck.
3. Definitive radiation therapy alone with altered fractionation in patients who are not candidates for concurrent chemotherapy and surgery (total laryngectomy) for salvage of radiation failures.[6,7]
4. Induction chemotherapy followed by concomitant chemotherapy and radiation. Laryngectomy is reserved for patients with less than a 50% response to chemotherapy or who have persistent disease after radiation.[6]
5. Clinical trials exploring novel targeted therapy, immunotherapy, novel chemotherapy, radiosensitizers, or particle-beam radiation therapy.[9]

For more information, see the Treatment Option Overview for Laryngeal Cancer section.

Role of Neck Dissection in the Post-Radiation Therapy Setting

A prospective randomized trial included 564 patients with head and neck cancer and N2 or N3 disease. Patients were assigned to undergo planned neck dissection or surveillance with positron emission tomography-computed tomography (PET-CT). With a median follow-up of 36 months, PET-CT resulted in fewer neck dissections compared with the surgical arm (54 vs. 221), with a 2-year survival rate of 84.9% versus 81.5%, respectively. The hazard ratio (HR)_death slightly favored PET-CT-guided surveillance and indicated noninferiority (upper boundary, 95% confidence interval for HR, <1.50; P = .004).[11][Level of evidence A1]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Forastiere AA, Zhang Q, Weber RS, et al.: Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 31 (7): 845-52, 2013.
2. Spaulding MB, Fischer SG, Wolf GT: Tumor response, toxicity, and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma. The Department of Veterans Affairs Cooperative Laryngeal Cancer Study Group. J Clin Oncol 12 (8): 1592-9, 1994.
3. Adelstein DJ, Saxton JP, Lavertu P, et al.: A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: preliminary results. Head Neck 19 (7): 567-75, 1997.
4. Jeremic B, Shibamoto Y, Milicic B, et al.: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 18 (7): 1458-64, 2000.
5. Bernier J, Domenge C, Ozsahin M, et al.: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350 (19): 1945-52, 2004.
6. Lefebvre JL, Pointreau Y, Rolland F, et al.: Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. J Clin Oncol 31 (7): 853-9, 2013.
7. MacKenzie RG, Franssen E, Balogh JM, et al.: Comparing treatment outcomes of radiotherapy and surgery in locally advanced carcinoma of the larynx: a comparison limited to patients eligible for surgery. Int J Radiat Oncol Biol Phys 47 (1): 65-71, 2000.
8. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 324 (24): 1685-90, 1991.
9. Adelstein DJ, Lavertu P, Saxton JP, et al.: Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer 88 (4): 876-83, 2000.
10. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
11. Mehanna H, Wong WL, McConkey CC, et al.: PET-CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer. N Engl J Med 374 (15): 1444-54, 2016.

Treatment of Stage IV Laryngeal Cancer

Supraglottis

Treatment options for stage IV cancer of the supraglottis include the following:

1. Concurrent chemoradiation therapy can be considered for patients who would require total laryngectomy for control of disease, including those with nonbulky T4a disease.[1]
2. Neoadjuvant chemotherapy followed by concurrent chemoradiation therapy. Laryngectomy is reserved for patients with less than a 50% response to chemotherapy or who have persistent disease after radiation.[1,2,3,4,5,6]
3. Definitive radiation therapy alone in patients who are not candidates for concurrent chemotherapy and surgery (total laryngectomy) for salvage of radiation failures.[7]
4. For patients with bulky T4 disease, surgery followed by postoperative radiation therapy (PORT) with or without concurrent chemotherapy based on pathological risk factors for large volume T4 disease.[8]
5. Clinical trials exploring novel targeted therapy, immunotherapy, novel chemotherapy, radiosensitizers, or particle-beam radiation therapy.[9]

Glottis

Treatment options for stage IV cancer of the glottis include the following:

1. Concurrent chemoradiation therapy can be considered for patients who would require total laryngectomy for control of disease, including those with nonbulky T4a disease.[1]
2. Neoadjuvant chemotherapy followed by concurrent chemoradiation therapy. Laryngectomy is reserved for patients with less than a 50% response to chemotherapy or who have persistent disease following radiation.[1,2,3,4,5,6]
3. Definitive radiation therapy alone in patients who are not candidates for concurrent chemotherapy and surgery (total laryngectomy) for salvage of radiation failures.[7]
4. For patients with bulky T4 disease, surgery (total laryngectomy) followed by PORT with or without concurrent chemotherapy based on pathological risk factors for large volume T4 disease.[8]
5. Clinical trials exploring novel targeted therapy, immunotherapy, novel chemotherapy, radiosensitizers, or particle-beam radiation therapy.[9]

Subglottis

Treatment options for stage IV cancer of the subglottis include the following:

1. Laryngectomy plus total thyroidectomy and bilateral tracheoesophageal node dissection usually followed by PORT with or without concurrent chemotherapy based on pathological risk factors.[10]
2. Concurrent chemoradiation therapy can be considered for patients who would require total laryngectomy for control of disease, including those with nonbulky T4a disease.[1]
3. Clinical trials exploring novel targeted therapy, immunotherapy, novel chemotherapy, radiosensitizers, or particle-beam radiation therapy.

For more information, see the Treatment Option Overview for Laryngeal Cancer section.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Forastiere AA, Zhang Q, Weber RS, et al.: Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 31 (7): 845-52, 2013.
2. Spaulding MB, Fischer SG, Wolf GT: Tumor response, toxicity, and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma. The Department of Veterans Affairs Cooperative Laryngeal Cancer Study Group. J Clin Oncol 12 (8): 1592-9, 1994.
3. Adelstein DJ, Saxton JP, Lavertu P, et al.: A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: preliminary results. Head Neck 19 (7): 567-75, 1997.
4. Jeremic B, Shibamoto Y, Milicic B, et al.: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 18 (7): 1458-64, 2000.
5. Bernier J, Domenge C, Ozsahin M, et al.: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350 (19): 1945-52, 2004.
6. Lefebvre JL, Pointreau Y, Rolland F, et al.: Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. J Clin Oncol 31 (7): 853-9, 2013.
7. MacKenzie RG, Franssen E, Balogh JM, et al.: Comparing treatment outcomes of radiotherapy and surgery in locally advanced carcinoma of the larynx: a comparison limited to patients eligible for surgery. Int J Radiat Oncol Biol Phys 47 (1): 65-71, 2000.
8. Bernier J, Cooper JS: Chemoradiation after surgery for high-risk head and neck cancer patients: how strong is the evidence? Oncologist 10 (3): 215-24, 2005.
9. Adelstein DJ, Lavertu P, Saxton JP, et al.: Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer 88 (4): 876-83, 2000.
10. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.

Treatment of Metastatic and Recurrent Laryngeal Cancer

Treatment Options for Metastatic and Recurrent Laryngeal Cancer

Treatment options for metastatic and recurrent laryngeal cancer include the following:

1. Surgery [1] and/or radiation therapy. Salvage is possible for failures of surgery alone or of radiation therapy alone, and further surgery [1] and/or radiation therapy should be attempted, as indicated. Selected patients may be candidates for partial laryngectomy after high-dose radiation therapy has failed.[2]
2. Radiation therapy. Re-irradiation for laryngeal salvage following radiation therapy failure has resulted in long-term survival in a small number of patients; it may be considered for small recurrences after radiation therapy, especially in patients who refuse or are not candidates for laryngectomy.[3]
3. Chemotherapy.
4. Immunotherapy.
   • Pembrolizumab.
   • Nivolumab.
5. Clinical trials for patients whose disease does not respond to combined radiation therapy and surgery.

For more information, see the Treatment Option Overview for Laryngeal Cancer section.

Chemotherapy

Platinum-based chemotherapy is often used as first-line treatment for patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck. A response of variable duration may be achieved after systemic chemotherapy.[4]

Evidence (chemotherapy):

1. In a phase III randomized trial of 442 patients with untreated metastatic or recurrent SCC of the head and neck, adding cetuximab to platinum plus fluorouracil compared with platinum plus fluorouracil alone improved overall survival (OS), with a median survival of 10.1 months versus 7.4 months (hazard ratio [HR] for death [HR_death], 0.80; 95% confidence interval [CI], 0.64–0.99; P = .04).[5]
   • Quality of life (QOL) was not adversely affected by adding cetuximab to this platinum-based regimen.[6]

   Tumor EGFR gene copy number was not found to be a predictive biomarker for the efficacy of cetuximab plus platinum and fluorouracil as first-line therapy for patients with recurrent or metastatic SCC of the head and neck.[7][Level of evidence A1]

2. A phase III, open-label, randomized trial demonstrated improvements in progression-free survival (PFS) for patients who received afatinib compared with patients who received methotrexate.[8]
   1. After a median follow-up of 6.7 months, the median PFS was 2.6 months (95% CI, 2.0–2.7) for the afatinib group and 1.7 months (95% CI, 1.5–2.4) for the methotrexate group (HR, 0.80; 95% CI, 0.65–0.98; P = .030).
   2. The most frequent grade 3 or grade 4 drug-related adverse events for patients treated with afatinib or methotrexate included the following:
      • Rash or acne (10% for afatinib vs. 0% for methotrexate).
      • Diarrhea (9% for afatinib vs. 2% for methotrexate).
      • Stomatitis (6% for afatinib vs. 8% for methotrexate).
      • Fatigue (6% for afatinib vs. 3% for methotrexate).
      • Neutropenia (<1% for afatinib vs. 7% for methotrexate).
   3. Overall serious adverse events occurred in 14% of patients treated with afatinib and 11% of patients treated with methotrexate.

Immunotherapy

Immunotherapy (inhibitor of the programmed death-ligand 1 [PD-L1] pathway) can be used after platinum-based failure in the metastatic or locally recurrent setting.[9,10]

Pembrolizumab

Pembrolizumab is a monoclonal antibody and an inhibitor of the programmed death (PD-1) pathway. There are two studies evaluating pembrolizumab in patients with incurable metastatic or recurrent head and neck squamous cell carcinoma.

Evidence (pembrolizumab as first-line therapy):

1. Performed at 200 sites in 37 countries, KEYNOTE-048 [NCT02358031] was a nonblinded, randomized, phase III study of patients with untreated locally incurable metastatic or recurrent head and neck squamous cell carcinoma.[11] A total of 882 patients were randomly assigned (1:1:1) to receive pembrolizumab alone (n = 301), pembrolizumab plus a platinum and fluorouracil (pembrolizumab with chemotherapy) (n = 281), or cetuximab plus a platinum and fluorouracil (cetuximab with chemotherapy) (n = 300). Investigators, patients, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. A total of 754 patients (85%) had a CPS of 1 or higher and 381 patients (43%) had a CPS of 20 or higher.

   The primary end points were OS and PFS. Progression was defined as radiographically confirmed disease progression or death from any cause, whichever came first, in the intention-to-treat population.

   • At second interim analysis, pembrolizumab alone improved OS versus cetuximab with chemotherapy in the population with a CPS of 20 or higher (median OS, 14.9 months vs. 10.7 months; HR, 0.61; 95% CI, 0.45–0.83; P = .0007) and in the population with a CPS of 1 or higher (12.3 months vs. 10.3 months; HR, 0.78; 95% CI, 0.64–0.96; P = .0086), and was noninferior in the total population (11.6 months vs. 10.7 months; HR, 0.85; 95% CI, 0.71–1.03).[11][Level of evidence A1]
   • At the second interim analysis, pembrolizumab with chemotherapy improved OS versus cetuximab with chemotherapy in the total population (13.0 months vs. 10.7 months; HR, 0.77; 95% CI, 0.63–0.93; P = .0034). At final analysis, pembrolizumab with chemotherapy improved OS versus cetuximab with chemotherapy in the population with a CPS of 20 or higher (14.7 months vs. 11.0 months; HR, 0.60; 95% CI, 0.45–0.82; P = .0004), and in the population with a CPS of 1 or higher (13.6 months vs. 10.4 months; HR, 0.65; 95% CI, 0.53–0.80; P < .0001).
   • At the second interim analysis, neither pembrolizumab alone nor pembrolizumab with chemotherapy improved PFS.
   • At final analysis, grade 3 or worse all-cause adverse events occurred in 164 of 300 patients (55%) in the pembrolizumab-alone group, 235 of 276 patients (85%) who received pembrolizumab with chemotherapy, and 239 of 287 patients (83%) who received cetuximab with chemotherapy.
   • Adverse events led to death in 25 patients (8%) in the pembrolizumab-alone group, 32 patients (12%) who received pembrolizumab with chemotherapy, and 28 patients (10%) who received cetuximab with chemotherapy.

Pembrolizumab plus a platinum and fluorouracil is an appropriate first-line treatment for patients with metastatic or recurrent head and neck squamous cell carcinoma. Pembrolizumab monotherapy is an appropriate first-line treatment for patients with PD-L1–positive metastatic or recurrent head and neck squamous cell carcinoma.

Evidence (pembrolizumab after progression on platinum-based treatment):

1. KEYNOTE-040 [NCT02252042], a randomized phase III trial, included patients with incurable recurrent or metastatic head and neck SCC who had received platinum-based treatment within 3 to 6 months.[9] Patients were randomly assigned to the pembrolizumab arm (200 mg every 3 weeks [247 patients]) or to the standard therapy arm of the investigator's choice (methotrexate, docetaxel, or cetuximab [248 patients]). Patients received treatment until progression or toxicity. The maximum duration of pembrolizumab was 24 months. The primary end point was OS in the intention-to-treat population.
   • The median OS was 8.4 months in the pembrolizumab arm versus 6.9 months in the standard therapy arm (HR, 0.80; 95% CI, 0.65–0.98; nominal P = .0161).[9][Level of evidence A1]
   • Pembrolizumab was associated with fewer grade 3 or higher adverse events (pembrolizumab, 13% vs. standard therapy, 36%). The most common treatment-related adverse events were hypothyroidism (13%) in the pembrolizumab arm and fatigue (18%) in the standard therapy arm.
   • In patients receiving pembrolizumab, there were four treatment-related deaths resulting from large intestinal perforation, Stevens-Johnson syndrome, and unspecified, malignant progression; two treatment-related deaths in the standard therapy arm resulted from malignant progression and pneumonia.
   • The PD-L1 combined positive score was 1 or higher in 79% of the patients in the pembrolizumab arm and 77% of the patients in the standard therapy arm.
   • Patients with PD-1 expression on their tumors or in the tumor microenvironment as noted by the PD-L1 combined positive score of 1 or higher (HR, 0.74; 95% CI, 0.58–0.93; nominal P = .0049) or a PD-L1 tumor proportion score of 50% or higher (HR, 0.53; 95% CI, 0.35–0.81; nominal P = .0014), and treated with pembrolizumab had reduced HR_death when compared with patients treated with standard therapy.

Nivolumab

Nivolumab is a fully human immunoglobulin G4 (IgG4) anti–PD-1 monoclonal antibody.

Evidence (nivolumab):

1. A phase III, open-label, randomized trial included 361 patients with recurrent SCC of the head and neck and disease progression within 6 months after platinum-based chemotherapy. Patients were assigned in a 2:1 ratio to receive nivolumab (at a dose of 3 mg/kg of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab) with a primary end point of OS.[10]
   • The median OS was 7.5 months (95% CI, 5.5–9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0–6.0) in the standard therapy group. OS was significantly longer with nivolumab than with the standard therapy (HR_death, 0.70; 97.73% CI, 0.51–0.96; P = .01), and the estimates of the 1-year survival rate were approximately 19% higher with nivolumab (36.0%) than with standard therapy (16.6%).[10][Level of evidence A1]
   • There was no difference in median PFS between groups. The rate of PFS at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy.
   • The response rate was 13.3% in the nivolumab group versus 5.8% in the standard therapy group.
   • Grade 3 or 4 treatment-related adverse events occurred in 13.1% of the patients in the nivolumab group compared with 35.1% in the standard therapy group.
   • QOL using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ), Core Module (QLQ-C30) and the Head and Neck Module (QLQ-H&N35) domains—including physical, role, social functioning, pain, sensory, and social contact problems—were stable in the nivolumab arm, but QOL was worse in the standard therapy group.
   • In the subgroup of patients with a PD-L1 expression level of 1% or higher, the HR_death among the patients treated with nivolumab versus standard therapy was 0.55 (95% CI, 0.36–0.83) compared with the subgroup of patients with a PD-L1 expression level of lower than 1% for whom the HR was 0.89 (95% CI, 0.54–1.45; P = .17 for interaction).

Salvage after previous combined total laryngectomy and radiation therapy is poor.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Wong LY, Wei WI, Lam LK, et al.: Salvage of recurrent head and neck squamous cell carcinoma after primary curative surgery. Head Neck 25 (11): 953-9, 2003.
2. Paleri V, Thomas L, Basavaiah N, et al.: Oncologic outcomes of open conservation laryngectomy for radiorecurrent laryngeal carcinoma: a systematic review and meta-analysis of English-language literature. Cancer 117 (12): 2668-76, 2011.
3. Wang CC, McIntyre J: Re-irradiation of laryngeal carcinoma--techniques and results. Int J Radiat Oncol Biol Phys 26 (5): 783-5, 1993.
4. Al-Sarraf M: Head and neck cancer: chemotherapy concepts. Semin Oncol 15 (1): 70-85, 1988.
5. Vermorken JB, Mesia R, Rivera F, et al.: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359 (11): 1116-27, 2008.
6. Mesía R, Rivera F, Kawecki A, et al.: Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 21 (10): 1967-73, 2010.
7. Licitra L, Mesia R, Rivera F, et al.: Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study. Ann Oncol 22 (5): 1078-87, 2011.
8. Machiels JP, Haddad RI, Fayette J, et al.: Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 16 (5): 583-94, 2015.
9. Cohen EEW, Soulières D, Le Tourneau C, et al.: Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 393 (10167): 156-167, 2019.
10. Ferris RL, Blumenschein G, Fayette J, et al.: Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 375 (19): 1856-1867, 2016.
11. Burtness B, Harrington KJ, Greil R, et al.: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 394 (10212): 1915-1928, 2019.

Latest Updates to This Summary (02 / 09 / 2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Laryngeal Cancer

Updated statistics with estimated new cases and deaths for 2024 (cited American Cancer Society as reference 1).

Treatment Option Overview for Laryngeal Cancer

Added Fluorouracil dosing as a new subsection.

Treatment of Metastatic and Recurrent Laryngeal Cancer

The Pembrolizumab subsection was extensively revised.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult laryngeal cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Laryngeal Cancer Treatment are:

• Andrea Bonetti, MD (Azienda ULSS 9 of the Veneto Region)
• Monaliben Patel, MD (University of Rochester Medical Center)
• Minh Tam Truong, MD (Boston University Medical Center)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Laryngeal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/head-and-neck/hp/adult/laryngeal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389189]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.

Last Revised: 2024-02-09